The present invention relates to a process for the preparation of 2-phenyl-imidazo[1,2-a]pyridine-3-acetamides.
More particularly, the invention relates to a process for the preparation of Zolpidem (N,N-dimethyl-6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide hemitartrate), a pharmaceutical compound with hypnotic-sedative activity at present widely used in clinic, disclosed in EP 50.563.
Zolpidem has the following structural formula: 
Zolpidem is the parent compound of a chemical class with hypnotic activity which has recently arisen interest: 2-phenyl-imidazo[1,2-a]pyridine-3-acetamides, having the following general formula: 
wherein X, Y, R1 and R2 are substituents widely documented in a number of patents and articles published in the last two decades, concerning the preparation of a great deal of derivatives as well as the hypnotic-sedative properties thereof.
The known processes for the preparation of Zolpidem are part of the general procedures used for the preparation of variously substituted imidazo[1,2-a]pyridine-3-acetamides. These syntheses differ in the procedure for the introduction of the acetamide chain at the 3- position of 6-methyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine, which molecule is common to all said processes.
6-Methyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine, in the following referred to as imidazo-pyridine for sake of shortness, can be obtained according to a procedure comprising condensation of a variously substituted 2-amino-pyridine with a suitably substituted xcex1-halo-acetophenone, which is prepared by halogenation of the corresponding substituted acetophenone (GB 991,589) or by reacting a suitably substituted benzene with an xcex1-halo-acetyl halide under the Friedel-Crafts acylation conditions (WO 00/08021) as reported in Scheme 1. 
The numerous works published concerning the functionalization of the midazo-pyridine at the 3-position 3 describe four synthetic routes, according to the following Scheme 2. 
2.1 Synthesis of Zolpidem via Mannich amino-methylation
This synthetic route involves the imidazo-pyridino-3-acetonitrile intermediate whose preparation is disclosed in GB 991,589 and GB 1,076,089.
This approach has subsequently been applied to the synthesis of the Zolpidem in EP 50.563, as shown in Scheme 3. 
The amino methylation of the imidazo-pyridine (step 1) yields the 3-dimethylamino derivative, which is alkylated with methyl iodide (step 2), to obtain the quaternary ammonium salt, which is then reacted with sodium cyanide (step 3) to give the corresponding nitrile. The acid hydrolysis of the nitrile yields the carboxylic acid (step 4) which is activated with carbonyldiimidazole (CDI), then treated with a dimethylamine excess (step 5) to obtain the corresponding dimethylamide (Zolpidem).
The use of methyl iodide (highly toxic, low-boiling alkylating agent) in the alkylation step and the nucleophilic substitution of the quaternary ammonium salt with sodium cyanide (which is per se a dangerous starting product) restricts the industrial application of this synthetic approach.
2.2 Synthesis of Zolpidem via Formylation
A second synthetic route (EP 92,459) shares with the above one the acetonitrile intermediate and the subsequent hydrolysis and amidation steps, but such intermediate is prepared by a different procedure (see the following Scheme 4). 
The imidazo-pyridine is formylated according to the Vilsmeier-Haack""s reaction (step 1) to obtain the aldehyde which is reduced with sodium borohydride (step 2) to yield the corresponding alcohol. This is reacted with p-toluenesulfonyl chloride in pyridine to obtain the quaternary ammonium salt (step 3) which is reacted with the cyanide ion (step 4), to yield the 3-acetonitrile derivative. The resulting intermediate is transformed into the acid with conventional methods, then is amidated to give Zolpidem.
Compared with the procedure described above (scheme 3), an alternative to the preparation of the quaternary ammonium salt has been found, which however still involves the critical use of cyanides.
2.3 Synthesis of Zolpidem by Pummerer Modified Reaction
This synthetic route, shown in Scheme 5, is described in Actual Chim Ther., 1991, 18, 215-39. 
The precursor of the acetamide chain used in this procedure is N,N-dimethylmethylsulfoxy-acetamide, which reacts with imidazopyridine in acid medium according to a modified procedure of the Pummerer reaction, to give the xcex1-methylmercaptoacetamido derivative, which is desulfonated with nickel-Raney to obtain Zolpidem.
This procedure, although being direct and requiring only two steps, is critical due to formation of methylmercaptan (toxic gas) from the reduction reaction, to the use of nickel-Raney (cancerogenic) and to the poor yield.
2.4 Synthesis of Zolpidem via Glyoxylic Acid and Derivatives
The synthetic routes making use of the reactivity of imidazo-pyridine toward glyoxylic acid and derivatives thereof are the easiest to carry out from the industrial point of view.
From the chemical standpoint, all of the procedures based on this type of reaction yield the xcex1-hydroxy-acetic intermediate (or a derivative thereof) which has to be reduced to obtain the desired product.
The synthetic general scheme general is reported in the following Scheme 6. 
R=H, alkyl (also mixed)
X=OH, O-alkyl, xe2x80x94N(CH3)2 
Two processes for the preparation of imidazo-pyridine derivatives, and particularly Zolpidem, follow said synthetic procedure.
The first process (FR 2,600,650) comprises the use of N,N-dimethyglyoxamide, prepared in situ from the corresponding acetal, which is in its turn prepared according to the following Scheme 7. 
The acetal is treated with concentrated hydrochloric acid in acetic acid, to obtain the glyoxylic amide which is then used for the functionalization of the imidazo-pyridine, as shown in the following Scheme 8. 
The xcex1-hydroxyacetamide resulting from the reaction (1) is treated with thionyl chloride to obtain the corresponding xcex1-chloro derivative, which is reduced with either a boron hydride, dithionite or a zinc/hydrochloric acid mixture to yield Zolpidem.
The second process (WO 00/08021) uses methyl glyoxalate or its methyl hemiacetal prepared according to the following Scheme 9. 
Imidazopyridine is reacted with glyoxylic acid methyl ester (or its hemiacetal) (step 1) to obtain the xcex1-hydroxyacetate derivative which is treated with the chloroiminium salt, prepared in situ from DMF and thionyl chloride, to give the corresponding xcex1-chloro-derivative (step 2). The latter is reduced with sodium formaldehyde sulfoxylate (or sodium hydroxymethanesulfinate) (step 3) and the resulting ester is treated gaseous dimethylamine in a polyhydroxylated solvent under mild pressure (step 4) to obtain Zolpidem.
In conclusion, all known synthesis of Zolpidem use either reagents commercially available with difficulty, toxic reagents, or industrially unsuitable procedures due to low yields and/or products with poor purity which should undergo repeated purification procedures.
It has now been found an efficient, convenient process for the preparation of 2-phenyl-imidazo[1,2-a]pyridine-3-acetamides, in particular Zolpidem.
According to the invention, 2-phenyl-imidazo[1,2-a]pyridine-3-acetamides of formula 5 
wherein
X is hydrogen, halogen, C1-C4 alkyl, C1-C6 alkoxy, CF3, CH3S, nitro, CH3SO2;
Y is hydrogen, a halogen atom or C1-C4 alkyl;
are prepared with a process which comprises:
a) reacting a 2-phenyl-imidazo[1,2-a]pyridine of formula 1 
xe2x80x83wherein X and Y have the meanings defined above, with an oxalate of formula 2 
xe2x80x83wherein R1 is a halogen or a carboxy-activating group, R2 is C1-C6 alkoxy, aralkoxy or phenoxy (both optionally substituted with C1-C6 alkyl or alkoxy), or is C1-C6 alkylamino or arylamino;
b) reducing the resulting compound of formula 3 
xe2x80x83wherein X and Y have the meanings defined above;
c) reacting the resulting compound of formula 4 
xe2x80x83or a reactive derivative thereof, with amines of formula NHR3R4 wherein R3 and R4, which can be the same or different, are hydrogen, C1-C5 alkyl, allyl, propargyl, C3-C6 cycloalkyl, benzyl, phenyl.
In the first step, imidazo-pyridine 1 is acylated with an oxalic acid mono-activated derivative 2 wherein R1 is halogen, for example chlorine or bromine, or a carboxy-activating group such as OSO2CH3, xe2x80x94OSO2Tol, xe2x80x94OPOCl2, xe2x80x94OCOR and the like.
The reaction is carried out in the presence of a base, for example tertiary amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine and the like.
Reaction solvents can be selected from aromatic hydrocarbons (such as toluene, xylene), esters (such as ethyl acetate, butyl acetate), chlorinated hydrocarbons (such as methylene chloride, chloroform, carbon tetrachloride, benzotrifluoride, chlorobenzene), ketones (such as acetone, methyl ethyl ketone, cyclohexanone, methyl isobutyl ketone), ethers (such as ethyl ether, isopropyl ether, tetrahydrofuran, dioxane), amides (such as N,N-dimethylformamide, N,N-dimethylacetamide), sulfoxides (dimethylsulfoxide) and the like, and they are used in ratios ranging from 1 to 10 parts by volumes (preferably from 2 to 5) per part of compound 1.
The reaction is carried out at xe2x88x9220xc2x0 C. to 80xc2x0 C., preferably at 10xc2x0 C. to 50xc2x0 C., using an amount of compound 2 and of base ranging from 1 to 2 equivalents, preferably from 1.2 to 1.5 equivalents.
Compound 3 is obtained in substantially quantitative yield after aqueous hydrolysis, separation of the phases and concentration to dryness of the organic phase.
The residue is crystallized from solvents selected from alcohols (such as methanol, ethanol, isopropanol, n-butanol), esters (such as ethyl acetate, butyl acetate), ketones (such as acetone, ethyl methyl ketone, methyl isobutyl ketone) and the like to obtain the pure product in yield above 90%, starting from imidazo-pyridine 1.
In the second step, the ketone is reduced to the corresponding alkane by reduction according to a known procedure, such as the Wolff-Kishner or Clemmensen reductions, or by catalytic hydrogenation with hydrogen or hydrogen donors, trialkylphosphites, lithium aluminium hydride and sodium borohydride derivatives, reduction of the corresponding tosylhydrazone, reduction of the corresponding dithioketal with Nickel-Raney, (J. March, Advanced Organic Chemistry, Ed 4, 1992).
In the case of Wolff-Kishner reduction, the reaction is carried out in water, ethylene glycol or mixtures thereof, preferably in water in ratios ranging from 0.5 to 3 parts by volumes (preferably from 0.8 to 1.7) per part of compound 3. The reaction is carried out at a temperature from 100 to 140xc2x0 C., preferably from 115xc2x0 C. to 125xc2x0 C., using sodium or potassium hydroxide in amounts ranging from 1 to 5 equivalents, preferably from 1 to 3, and hydrazine in amounts from 0.9 to 2.0 equivalents, preferably 1.0 equivalents.
Compound 4 is obtained in solution in substantially quantitative yield after dilution with water and alcohols and acidification with mineral acids (hydrochloric acid, hydrobromic, sulfuric, methanesulfonic and the like) or with organic acids (formic acid, acetic acid and the like), filtration and drying in a yield above 90%.
In the third step consists an amidation reaction is carried out with any suitable method, for example by reaction of the acid 4 with carbonyldiimidazole or dicyclohexylcarbodiimide and subsequent treatment with N,N-dimethylamine; or by transformation of the acid 4 into the corresponding chloride with thionyl chloride, oxalyl chloride or phosphorous pentachloride and subsequent treatment with N,N-dimethylamine; alternatively, through an intermediate mixed anhydride (organic or inorganic) or through an alkyl ester (methyl, ethyl, allyl and the like) or aryl ester (benzyl, phenyl, 4-methoxyphenyl, 3,4,5-trimethoxyphenyl and the like) and by subsequent treatment with the amine.
N,N-dimethylamine can be used as gas or can be formed in situ by treating its hydrochloride with an organic or inorganic base, or in aqueous or methanol solution, or in an aprotic solvent.
Under the best operative conditions, this method provides Zolpidem of suitable quality and in yields above 80%, starting from imidazo-pyridine.